Myelodysplastic Syndromes (MDS)
Conditions
Keywords
Myelodysplastic Syndromes (MDS), Refractory, LBH589
Brief summary
This will be a single arm Phase II study.
Detailed description
LBH589 (20 mg PO) will be administered three times a week on Monday, Wednesday and Friday. Treatment will be given over 21 days followed by a 7 day rest period and repeated every 28 days. Patients will be assessed for toxicity on an ongoing basis and disease assessment will be determined every 2 treatment cycles (8 weeks). Patients will be allowed to continue on treatment for a maximum of eight four week treatment cycles. Treatment will be discontinued if there is evidence of disease progression, unacceptable toxicity and/or at the discretion of the investigator.
Interventions
DRUGPanobinostat
Panobinostat(20 mg or 30 mg PO) will be administered three times a week on Monday, Wednesday and Friday. Treatment will be given over 21 days followed by a 7 day rest period and repeated every 28 days. Patients will be assessed for toxicity on an ongoing basis and disease assessment will be determined every 2 treatment cycles (8 weeks). Patients will be allowed to continue on treatment for a maximum of eight four week treatment cycles. Treatment will be discontinued if there is evidence of disease progression, unacceptable toxicity and/or at the discretion of the investigator.
Sponsors
Novartis Pharmaceuticals
SCRI Development Innovations, LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytological documented diagnosis of myelodysplastic syndrome (MDS). * Male or female patients aged \>= 18 years old. * MDS patients who have failed hypomethylating (azacitidine or decitabine) therapy. * Patients with 5q-cytogenic abnormalities must also have progressed on or been intolerant to lenalidomide. * Patients with up to and including 30% blasts (FAB RAEB-T) will be eligible to enroll. * CMML with \>= 5% blasts will be eligible to enroll. * ECOG PS 0, 1 or 2. * Laboratory values must be as follows: Bilirubin \<= 1.5 mg/dL AST/SGOT \<= 2.5 x ULN ALT/SGPT Creatinine \<= 2.0 mg/dL or 24-hour Creatinine Clearance \>= 50 ml/min Albumin \>= 3 g/dL Potassium \>= lower limit normal (LLN) Phosphorous \>= LLN Calcium \>= LLN Magnesium \>= LLN * Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to start of treatment. * Life expectancy \>= 12 weeks.
Exclusion criteria
* Prior treatment with an HDAC inhibitor. * Prior intensive chemotherapy or high dose ara-C (\>= 1 gm/m2) * More than one prior single agent chemotherapy regimen. Prior hydroxyurea for cytoreduction will be permitted however. * Impaired cardiac function * Active CNS disease, including leptomeningeal metastases. * Unresolved diarrhea \> CTCAE grade 1. * Chemotherapy, investigational drug therapy, major surgery \< 4 weeks prior to starting study drug or patients that have not recovered from side effects of previous therapy. * Patient is \< 5 years free of another primary malignancy except if the other primary malignancy is not currently clinically significant or requiring active intervention, or if other primary malignancy is a basal cell skin cancer or a cervical carcinoma in situ. Existence of any other malignant disease is not allowed. * Women who are pregnant or breast feeding or women of childbearing potential (WOCBP) not willing to use a double barrier method of contraception during the study and 3 months after the end of treatment. One of these methods of contraception must be a barrier method. * Male patients whose sexual partners are WOCBP not using a double method of contraception during the study and 3 months after the end of treatment. One of these methods must be a condom. * Patients with gastrointestinal (GI) tract disease, causing the inability to take oral medication, malabsorption syndrome, a requirement for intravenous (IV) alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn's disease, ulcerative colitis). * Other concurrent severe, uncontrolled systemic fungal, bacterial, viral or other infection or intercurrent illness, including but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * Patients with uncontrolled coagulopathy. * Abnormal thyroid function (TSH or free T4) detected at screening. Patients with known hypothyroidism who are stable on thyroid replacement are eligible.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (CR, Marrow CR + PR) of LBH in Patients With Relapsed or Refractory MDS. | Every 8 weeks up to 24 months on-study. | Overall response rate (ORR) is defined by the modified International Working Group (IWG) Response Criteria for MDS. In the marrow, Complete Response (CR) is \<= 5% blasts present with normal maturation of all cell lines. In peripheral blood, CR is defined as hemoglobin \>= 11 g/dL, ANC \>= 1000/mL, and platelets \>= 100,000 with 0% blasts present. Partial Response (PR) is defined the same as CR with blasts decreased by \>= 50% and \>= 5% blasts in the marrow. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hematologic Improvement, Including Transfusion Independence | Every 8 weeks up to 24 months on-study | Hematologic measures will include total WBC and platelets |
| Duration of Response | Every 8 weeks up to 24 months on-study | Duration of response is defined as the time from when objective response is realized until time to first documented disease progression. Disease progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Objective Response = CR + PR. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI or CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions. |
| Time to Disease Progression | Every 8 weeks up to 24 months on-study, every 3 months in follow-up until progression of disease | Time to disease progression is defined as the time between day 1 cycle 1 and time to first documented disease progression. Disease progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
| Median Overall Survival | 24 months on-study, patients followed every 3 months in follow-up | The Length of Time, in Months, That Patients Were Alive From Their First Date of Protocol Treatment Until Death |
| Safety and Tolerability of LBH589 in Patients With Relapsed/Refractory MDS by Measuring the Number of Participants With Adverse Events | 24 months | The reported incidence of AEs and SAEs with an onset on or after the initiation of therapy was graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 |
| Median Time to Treatment Failure | 24 months | Time to treatment failure is defined as measuring the time between cycle 1 day 1 to discontinuation for any reason. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Panobinostat 30 mg Panobinostat(30 mg PO) will be administered three times a week on Monday, Wednesday and Friday. Treatment will be given over 21 days followed by a 7 day rest period and repeated every 28 days. Patients will be assessed for toxicity on an ongoing basis and disease assessment will be determined every 2 treatment cycles (8 weeks). Patients will be allowed to continue on treatment for a maximum of eight four week treatment cycles. Treatment will be discontinued if there is evidence of disease progression, unacceptable toxicity and/or at the discretion of the investigator. | 16 |
| Panobinostat 20 mg Panobinostat(20 mg PO) will be administered three times a week on Monday, Wednesday and Friday. Treatment will be given over 21 days followed by a 7 day rest period and repeated every 28 days. Patients will be assessed for toxicity on an ongoing basis and disease assessment will be determined every 2 treatment cycles (8 weeks). Patients will be allowed to continue on treatment for a maximum of eight four week treatment cycles. Treatment will be discontinued if there is evidence of disease progression, unacceptable toxicity and/or at the discretion of the investigator. | 10 |
| Total | 26 |
Baseline characteristics
| Characteristic | Panobinostat 30 mg | Panobinostat 20 mg | Total |
|---|---|---|---|
| Age, Continuous | 75 years | 74 years | 75 years |
| Region of Enrollment United States | 16 participants | 10 participants | 26 participants |
| Sex: Female, Male Female | 1 Participants | 6 Participants | 7 Participants |
| Sex: Female, Male Male | 15 Participants | 4 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 9 / 10 | 15 / 16 |
| serious Total, serious adverse events | 3 / 10 | 6 / 16 |
Outcome results
Primary
Overall Response Rate (CR, Marrow CR + PR) of LBH in Patients With Relapsed or Refractory MDS.
Overall response rate (ORR) is defined by the modified International Working Group (IWG) Response Criteria for MDS. In the marrow, Complete Response (CR) is \<= 5% blasts present with normal maturation of all cell lines. In peripheral blood, CR is defined as hemoglobin \>= 11 g/dL, ANC \>= 1000/mL, and platelets \>= 100,000 with 0% blasts present. Partial Response (PR) is defined the same as CR with blasts decreased by \>= 50% and \>= 5% blasts in the marrow.
Time frame: Every 8 weeks up to 24 months on-study.
Population: All evaluable patients assessed for response prior to early study termination - one patient in each arm was not evaluable due to coming off-study prior to assessment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Panobinostat 30 mg | Overall Response Rate (CR, Marrow CR + PR) of LBH in Patients With Relapsed or Refractory MDS. | 0 participants |
| Panobinostat 20 mg | Overall Response Rate (CR, Marrow CR + PR) of LBH in Patients With Relapsed or Refractory MDS. | 0 participants |
Secondary
Duration of Response
Duration of response is defined as the time from when objective response is realized until time to first documented disease progression. Disease progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Objective Response = CR + PR. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI or CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions.
Time frame: Every 8 weeks up to 24 months on-study
Population: Study terminated early, no results are available for this endpoint as the analysis was not done
Secondary
Hematologic Improvement, Including Transfusion Independence
Hematologic measures will include total WBC and platelets
Time frame: Every 8 weeks up to 24 months on-study
Population: Study terminated early, no results are available for this endpoint as the analysis was not done
Secondary
Median Overall Survival
The Length of Time, in Months, That Patients Were Alive From Their First Date of Protocol Treatment Until Death
Time frame: 24 months on-study, patients followed every 3 months in follow-up
Population: Study terminated early, no results are available for this endpoint as the analysis was not done
Secondary
Median Time to Treatment Failure
Time to treatment failure is defined as measuring the time between cycle 1 day 1 to discontinuation for any reason.
Time frame: 24 months
Population: Study terminated early, no results are available for this endpoint as the analysis was not done
Secondary
Safety and Tolerability of LBH589 in Patients With Relapsed/Refractory MDS by Measuring the Number of Participants With Adverse Events
The reported incidence of AEs and SAEs with an onset on or after the initiation of therapy was graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0
Time frame: 24 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Panobinostat 30 mg | Safety and Tolerability of LBH589 in Patients With Relapsed/Refractory MDS by Measuring the Number of Participants With Adverse Events | 15 Participants |
| Panobinostat 20 mg | Safety and Tolerability of LBH589 in Patients With Relapsed/Refractory MDS by Measuring the Number of Participants With Adverse Events | 9 Participants |
Secondary
Time to Disease Progression
Time to disease progression is defined as the time between day 1 cycle 1 and time to first documented disease progression. Disease progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: Every 8 weeks up to 24 months on-study, every 3 months in follow-up until progression of disease
Population: Study terminated early, no results are available for this endpoint as the analysis was not done.